The present invention relates to novel fatty acid analogous which can be used for the treatment and/or prevention of obesity, fatty liver and hypertension. Further, the invention relates to a nutritional composition comprising such fatty acid analogues, and a method for reducing the total weight, or the amount of adipose tissue in an animal. The invention also relates to a method for improving the quality of product such as meat, milk and eggs.
Hyperlipidemia and obesity afflict an increasing proportion of the population in Western societies and are associated with the development of serious conditions such as atherosclerosis, hypertension, fatty liver and insulin resistance. These conditions may eventually lead to the clinical manifestations of coronary heart diseases (CD) and non-insulin dependent diabetes mellitus (NIDDM).
Treatment with modified fatty acids represent a new way to treat these diseases.
EP 345.038 describes the use of non-xcex2-oxidizable fatty acid analogues for the treatment of hyperlipidaemic conditions and for reducing the concentration of cholesterol and triglycerides in the blood of mammals.
PCT/NO95/00195 describes alkyl-Sxe2x80x94CH2COOR and alkyl-Sexe2x80x94CH2COOR for the inhibition of the oxidative modification OF ldl.
It has now been found that the analogues described in the prior art publication mentioned above, i.e. non-xcex2-oxidizable fatty acids substituted with Sulphur or Selenium in the 3-position have broader area of applications.
Further, we have now synthesized and characterized novel fatty acid analogues which impose an effect on obesity, hypertension and fatty liver.
In feeding experiments with the fatty acid analogues in accordance with the present invention, the results show that these compounds lower the adipose tissue mass and body weight, and are thus potent drugs for the treatment of obesity and overweight.
Further, we have shown that the fatty acid analogues are potent antidiabetic compounds, with a profound effect on the levels of glucose and insulin.
Further, the compounds have been proved to have an favourable effect on restenosis, and exhibit good anti-oxidative properties.
Obesity is a chronic disease that is highly prevalent in modern society and is associated not only with a social stigma, but also with decreased life span and numerous medical problems, including adverse psychological development, reproductive disorders such as polycystic ovarian disease, dermatological disorders such as infections, varicose veins, Acanthosis nigricans, and eczema, exercise intolerance, diabetes mellitus, insulin resistance, hyper-tension, hypercholesterolemia, cholelithiasis, osteoarthritis, orthopedic injury, thromboembolic disease, cancer, and coronary heart disease.
Existing therapies for obesity include standard diets and exercise, very low calorie diets, behavioral therapy, pharmacotherapy involving appetite suppressants, thermogenic drugs, food absorption inhibitors, mechanical devices such as jaw wiring, waist cords and balloons, and surgery. Caloric restriction as a treatment for obesity causes catabolism of body protein stores and produces negative nitrogen balance.
Considering the high prevalence of obesity in our society and the serious consequences associated therewith as discussed above, any therapeutic drug potentially useful in reducing weight of obese persons could have a profound beneficial effect on their health. There is a need in the art for a drug that will reduce total body weight of obese subjects toward their ideal body weight without significant adverse side effects, and which also will help the obese subject to maintain the reduced weight level.
It is therefore an object of the present invention to provide a treatment regimen that is useful in returning the body weight of obese subjects toward a normal, ideal body weight.
It is another object to provide a therapy for obesity that results in maintenance of the lowered body weight for an extended period of time. Further, is is an object to reduce or inhibit the weight gain normally induced by fat rich diets.
It is yet another object to prevent obesity and, once treatment has begun, to arrest progression or prevent the onset of diseases that are the consequence of, or secondary to, the obesity, such as hypertension and fatty liver. These and other objects will be apparent to those of ordinary skill in the art.
The obesity herein may be due to any cause, whether genetic or environmental. Examples of disorders that may result in obesity or be the cause of obesity include overeating and bulimia, polycystic ovarian disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich""s syndrome, Type II diabetics, GH-deficient subjects, normal variant short stature, Turner""s syndrome, and other pathological conditions showing reduced metabolic activity.
Increased blood pressure is a common condition in the developed countries of the world where, in very broad terms, the population eat too much and do not take sufficient exercise. Hypertension can have a variety of uncomfortable and dangerous side effects and it is seen as a major risk factor in relation to coronary heart disease. Hypertension can be associated with specific causes such as kidney disease or adrenal tumours but in most instances it is not. Obesity is regarded as a risk factor in relation to hypertension and a first line strategy in relation to obese hypertensive patients is to suggest weight reduction. It is therefore reasonable to anticipate that the present compounds, e.g. TTA and TSA which can have an effect on obesity, will reduce hypertension.
Specific ailments attributable to hypertension include heart failure, myocardial infarction, rupture or thrombus of the blood vessels in the brain, and kidney damage.
It is therefore an object of the present invention to provide a treatment regimen that is useful in lowering the blood pressure.
The mechanism of production of fatty hepatosis is not entirely clear, but appears to be a combinaticn of several factors, such as sparing action of ethanol oxidation on utilization of liver triacylglycerols, excessive mobilization of triacylglycerols from adipose tissue to the liver caused in part by action of ethanol in triggering release of hormones, and failure to synthesize sufficient lipoprotein for transport of triacylglycerols because of alterations of amino acid availability.
Fatty cirrhosis is characterized by the liver cells being infiltrated with fat (triacylglycerols). The infiltration usually being due to alcohol ingestion.
The explanation for the ethanol induced increase in hepatic deposition of fat is still not very well understood. However, most investigators believe that ethanol inhibits hepatic fatty acid oxidation which secondarily causes fatty acids to be stored as triacylglycerol.
Fatty liver as a concomitant of the ingestion of high fat diets, alcohols or chlorinated hydrocarbons is a well-known phenomenon. Chronic intake of ethanol results in, among other things, hepatic injury to the accumulation of triglycerides and eventually, cirrhosis.
It is thus an object of the present invention to provide a treatment regimen that is useful in lowering the concentration of triacylglycerols in the liver. It is anticipated that such a regimen will provide an inhibiting effect on the development of a fatty liver condition, and also be suited as a method for the treatment of the manifested disease.
The compounds of the present invention both activates the xcex2-oxidation, and also reduces the concentration of triglycerieds in the liver.
Minor modifications of natural fatty acids, sulphur, selenium or oxygen replacing one or more of carbons in the fatty acid backbone. The compounds defined by the formula I have properties which give them a unique combination of biological effects.
Tetradecylthioacetic acid (TTA) is most thoroughly studied and we have shown several beneficial effects in various test animals.
The studies have shown that TTA has properties very similar to natural fatty acids, the main difference being that TTA is not oxidised by the mitochondrial xcex2-oxidation system. However, the presence of compounds of the present invention have been shown to increase the xcex2-oxidation of other (non-substituted fatty acids).
Administration of TTA to rats for 12 weeks nearly doubled the hepatic and plasma content of monounsaturated fatty acids (mainly oleic acid), while polyunsaturated fatty acids (mainly linoleic acid and DHA) decreased. Thus the compound of the present invention modifies the composition of the lipids in various tissues. It is also shown that the present compounds modifies the fat content, and it is anticipated that the present compounds also will modify the fat distribution.
Feeding moderate doses of TTA to animals like rats, mice, rabbits and dogs decreased both plasma cholesterol and triacylglycerol levels within days of treatment. We have also shown the same effect for TSA, and compounds of the present invention with Sulphur substituted in positions 5 or 7 have been shown to increase the xcex2-oxidation and it is thus anticipated that also these fatty acid analogous will lower the plasma levels of triglycerides and cholesterol. TTA and TSA are far more potent in this respect than polyunsaturated fatty acids like EPA.
As mentioned above, an important mechanism of action of 3-thia fatty acids is a significant increased mitochondrial fatty acid oxidation reducing the availability of fatty acids for esterification. The synthesis of triacylglycerol and cholesterol is reduced and the secretion of VLDL from the liver is decreased (10). This has the effect of reducing the production of LDL. All these effects seem to be at least partly mediated by peroxisome proliferator activated receptors (PPAR), ubiquitous transcription factors involved in the regulation of lipid metabolism. We have shown that TTA is a potent ligand of PPARxcex1, a transcription factor regulating the catabolism of fatty acids and eicosanoids, and a less potent ligand of PPARxcex3, which is involved in the regulation of adipocyte differentiation.
Obesity is a common feature of non insulin dependent diabetes mellitus (NIDDM) and a risk factor for its development. NIDDM is often linked to hypertension, dyslipidemia, elevated levels of plasma free fatty acids and an increased risk of cardiovascular disease. NIDDM patients are characterised by resistance to insulin action on glucose uptake in peripheral tissues and dysregulated insulin secretion.
We have shown that TTA decrease hyperinsulinemia and markedly improved insulin action on glucose utilisation. TTA did also prevent diet-induced insulin resistance. In contrast to the prior known antidiabetic glitazones TTA did not increase body weight gain.
These effects may at least partly be explained by increased influx of fatty acids and enhanced fatty acid oxidation in the liver. The data thus suggest a role for TTA in both lipid and glucose homeostasis in vivo.
As clearly shown in the experimental section the compounds of the present invention inhibit an increase in the body weight and adipose tissue mass of animals given either a high fat or a high sucrose diet. This make the compounds of the present invention very suitable as pharmaceutical and/or nutritional agents for the treatment of obesity, i.e. the compounds can be used as a slimming agent to provide a body weight or adipose tissue weigh reduction.
Further the compounds of the present invention can be used as an anti-diabetic drug by reducing the concentration of glucose in the blood. We have also shown that the compounds of the present invention reduce the plasma concentration of insulin in hyperinsulineamic animals. For animals which possesses a reduces sensitivity to insulin, the compounds of the present invention have been shown to strengthen the effect of endogenous insulin.
The term  less than  less than metabolic syndrome greater than  greater than  is used to describe a multimetabolic syndrome which is inter alia characterised by hyperinsulinemia, insulin resistance, obesity, glucose intolerance, Type 2 diabetes mellitus, dyslipidemia or hypertension.
As indicated above the compounds of the present invention have been shown to provide a positive effect on all the conditions mentioned above, i.e. by regulating both the glucose and lipid homeostasis, and thus it is anticipated that the compounds of the present invention will be suitable agents for the regulation of the above defined metabolic disease (sometimes called syndrome X).
The present invention discloses that modified fatty acid analogues at non-cytotoxic concentrations can be used for the treatment and/or prevention of obesity, hypertension and fatty liver.
The present invention relates to the use of fatty acid analogues of the general formula (I):
CH3xe2x80x94[CH2]mxe2x80x94[xixe2x80x94CH2]nxe2x80x94COOR
wherein n is an integer from 1 to 12, and
wherein m is an integer from 0 to 23, and
wherein i is an odd number and indicates the position relative to COOR, and
wherein Xi independent of each other are selected from the group comprising O, S, SO, SO2, Se and CH2, and
wherein R represents hydrogen or C1-C4 alkyl,
with the proviso that at least one of the Xi is not CH2,
or a salt, prodrug and complex thereof, for the preparation of a pharmaceutical composition for the treatment and/or prevention of obesity.
In particular, the invention relates to the use of a compound of the general formula I wherein mxe2x89xa713. That is a compound which contains at least 14 carbons on the xcfx89 side of the X group.
A presently preferred embodiment of the invention is the use of a compound of formula I wherein Xi=3 is selected from the group consisting of O, S, SO, SO2 and Se, and wherein Xi=5xe2x88x9225 is CH2.
Tetradecylthioacetic acid (TTA) and Tetradecylselenioacetic acid (TSA), i. e. Xi=3 are Sulphur and Selenium, respectively is presently preferred compounds.
Furthermore, the present invention relates to the use of a compound of the formula I for the preparation of a pharmaceutical composition for the treatment and/or prevention of hypertension.
A further aspect of the invention relates to the use of a compound of the formula I for the preparation of a pharmaceutical composition for the treatment and/or prevention of fatty liver.
Still a further aspect of the invention relates to the use a compound of the formula I for the preparation of a pharmaceutical composition for the treatment and/or prevention of the multi metabolic syndrome termed  less than  less than metabolic syndrome greater than  greater than  which is inter alia characterised by hyperinsulinemia, insulin resistance, obesity, glucose intolerance, Type 2 diabetes mellitus, dyslipidemia and/or hypertension.
We have also synthesised and characterised novel fatty acid analogues, and thus in accordance with the present invention there is provided novel compounds of the formula I:
CH3xe2x80x94[CH2]mxe2x80x94[xixe2x80x94CH2]nxe2x80x94COOR
wherein n is an integer from 1 to 12, and
wherein m is an integer from 0 to 23, and
wherein i is an odd number and indicates the position relative to COOR, and
wherein Xi independent of each other are selected from the group comprising O, S, SO, SO2, Se and CH2, and
wherein R represents hydrogen or C1-C4 alkyl,
with the proviso that at least one of the Xi is not CH2.
A further aspect of the invention relates to a method for the treatment or prevention of an obese or overweight condition, said method comprising the step of administering to an animal in need thereof an effective amount of fatty acid analogues of the general formula (I):
CH3xe2x80x94[CH2]mxe2x80x94[xixe2x80x94CH2]nxe2x80x94COOR
wherein n is an integer from 1 to 12, and
wherein m is an integer from 0 to 23, and
wherein i is an odd number and indicates the position relative to COOR, and
wherein Xi independent of each other are selected from the group comprising O, S, SO, SO2, Se and CH2, and
wherein R represents hydrogen or C1-C4 alkyl,
with the proviso that at least one of the Xi is not CH2,
or a salt, prodrug and complex thereof.
In accordance with the method indicated above, preferred embodiments are as follows:
said animal is a human.
said animal is an agricultural animal, such as gallinaceous birds, bovine, ovine, caprine or porcine mammals.
said animal is a domestic or pet animal, such as dog or cat.
said animal is a fish or shellfish, such as salmon, cod, Tilapia, clams, oysters, lobster or crabs.
The treatment involves administering to a patient in need of such treatment a therapeutically effective concentration which is maintained substantially continuously in the blood of the animal for the duration of the period of its administration.
Further, the invention relates to a pharmaceutical composition for the prevention and/or treatment of obesity, hypertension or fatty liver. Preferably, the pharmaceutical composition comprises in admixture with the fatty acid analogues a pharmaceutically acceptable carrier or excipient.
The invention also relates to a nutritional composition comprising an amount of fatty acid analogues of the general formula (I) effective to reduce, or to prevent an increase in, the total body weight or the total body fat mass in a human or non-human animal, and a method for producing weigh loss or a reduction of the fat mass in a human or non-human animal in need thereof, comprising administering thereto an effective amount of a composition comprising fatty acid analogues of the general formula (I).
Preferred embodiments relate to a conditions wherein the animal has developed an obese condition or is low energy adapted.
Still another embodiment of the invention relates to the modification of the fat distribution, concentration and content of animals in order to improve the quality of the meat, visually, nutritionally and customer acceptability or product such as milk and eggs.
Preferred embodiments include agricultural animals, such as gallinaceous birds, bovine, ovine, caprine or porcine mammals, or fish or shellfish, such as salmon, cod, Tilapia, clams, oysters, lobster or crabs.